Physical and functional interactions between LDLR family members and CXCR4 in breast cancer.

Jiankang Zhang, Jinxiao Chen, Da Wo, En Ma, Hongwei Yan, Jun Peng, Dan-Ni Ren, Weidong Zhu
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Abstract

C-X-C chemokine receptor type 4 (CXCR4) belongs to the seven-span G protein-coupled receptor family and plays an important role in promoting cancer metastasis. The single-span receptor, low-density lipoprotein receptor-related protein 6 (LRP6) is commonly considered to be a co-receptor of Wnt and plays an indispensable role during animal development. We recently demonstrated that LRP6 directly binds to CXCR4 via its ectodomain and prevents CXCR4-induced breast cancer metastasis. As a result of structural similarity, LRP6 is also categorized within the low-density lipoprotein receptor (LDLR) family that is involved in lipoprotein transport. We therefore explored whether other LDLR family members could interact with CXCR4. Immunoprecipitation and western blotting analysis showed that LDLR and very low-density lipoprotein receptor (VLDLR) physically interacted with CXCR4. Although stromal cell-derived factor 1/CXCR4 signaling was inhibited by LDLR and LRP1, it was promoted by VLDLR, LRP8 and apolipoprotein E, a general agonist of the LDLR family. Furthermore, breast cancer patients with high CXCR4 expression exhibited the worst prognosis only when combined with high levels of VLDLR/LRP8/apolipoprotein E or low expression of LDLR/LRP1, further suggesting distinct positive and negative roles of LDLR family members in regulating CXCR4. Additional members of the LDLR family, SORL1 and LRP2, also showed a negative correlation with CXCR4 in the prognosis of breast cancer patients. The findings of the present study show that the LDLR family can regulate CXCR4, endowing its members with a previously undescribed role, also suggesting their potential as new breast cancer therapeutic targets and prognostic markers.

乳腺癌中 LDLR 家族成员与 CXCR4 之间的物理和功能相互作用
C-X-C 趋化因子受体 4 型(CXCR4)属于七跨 G 蛋白偶联受体家族,在促进癌症转移方面发挥着重要作用。单跨受体低密度脂蛋白受体相关蛋白6(LRP6)通常被认为是Wnt的共受体,在动物发育过程中发挥着不可或缺的作用。我们最近证实,LRP6 可通过其外结构域直接与 CXCR4 结合,并阻止 CXCR4 诱导的乳腺癌转移。由于结构相似,LRP6 也被归入参与脂蛋白转运的低密度脂蛋白受体(LDLR)家族。因此,我们探讨了其他 LDLR 家族成员是否能与 CXCR4 相互作用。免疫沉淀和 Western 印迹分析表明,LDLR 和极低密度脂蛋白受体(VLDLR)与 CXCR4 有物理相互作用。虽然基质细胞衍生因子 1/CXCR4 信号传导受到 LDLR 和 LRP1 的抑制,但 VLDLR、LRP8 和脂蛋白 E(一种 LDLR 家族的通用激动剂)却能促进这种信号传导。此外,CXCR4高表达的乳腺癌患者只有在同时具有高水平的VLDLR/LRP8/脂蛋白E或低水平的LDLR/LRP1表达时才会表现出最差的预后,这进一步表明LDLR家族成员在调节CXCR4方面具有不同的积极和消极作用。LDLR 家族的其他成员 SORL1 和 LRP2 在乳腺癌患者的预后中也与 CXCR4 呈负相关。本研究的结果表明,LDLR 家族可以调控 CXCR4,赋予其成员以前未曾描述过的作用,也表明它们有可能成为新的乳腺癌治疗靶点和预后标志物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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